The goal of this proposal is to develop physical understanding of and therapies for the failure of mucus clearance in patients with chronic bronchitic (CB) diseases, where mucus becomes sticky and adheres to the epithelial cell surface periciliary layer (PCL). We hypothesize that a unifying feature of CB diseases is dehydration of mucus that reflects common elements of pathogenesis in both genetic (e.g., cystic fibrosis) and environmental (e.g., cigarette smoke-induced) forms of CB. We hypothesize that the failure of CB mucus clearance is due to the higher adhesion and cohesion strengths between CB mucus and PCL that reflects mucus dehydration. In Sp. Aim 1, we will develop experiments, such as peel tests and cavitation rheology technique (CRT) in cultured cell preparations, which would allow us for the first time to measure the adhesion strength between mucus and PCL, the cohesion strength of mucus at different mucus concentrations, and crack propagation rates. Both the adhesion and cohesion strength will be quantified systematically and related to the viscoelastic properties of mucus in corresponding conditions. In Sp. Aim 2, we will measure mucus adhesion and cohesion in freshly excised ainways from human subjects with cigarette smoke-induced CB and CF, and compare data with cell culture model data. We will also test the relevance of a mouse model of airways mucus adhesion, the pENaC transgenic mouse, to human diseases. In Sp. Aim 3, we will test combinations of hydrating and mucolytic agents for therapeutic activity in CB subjects. This Aim will progress single agents/combinations from in vitro testing in cultured cells, using peel test and CRT measurements, to combination therapies in acute and 2 week in vivo testing in the (3ENaC mouse model. The overall goal of the project is to have a novel combination therapy identified for clinical testing in CB subjects within 2 years. RELEVANCE (See Instructions): Chronic bronchitis (CB) is caused by both genetic and environmental factors and affects more than 14 million Americans. Currently, there is little knowledge about the mechanism/or treatment ofthe abnormal airway sections that adhere to ainway surfaces in CB. We propose to utilize novel concepts from polymer physics and methodologies from material sciences to develop much needed effective therapies for CB.